Research

JAMA | Original Investigation

Effect of Intravenous Ferric Carboxymaltose on Hemoglobin

Response Among Patients With Acute Isovolemic Anemia
Following Gastrectomy
The FAIRY Randomized Clinical Trial
Young-Woo Kim, PhD; Jae-Moon Bae, PhD; Young-Kyu Park, PhD; Han-Kwang Yang, PhD; Wansik Yu, PhD; Jeong Hwan Yook, PhD; Sung Hoon Noh, PhD;
Mira Han, MS; Keun Won Ryu, PhD; Tae Sung Sohn, PhD; Hyuk-Joon Lee, PhD; Oh Kyoung Kwon, PhD; Seung Yeob Ryu, PhD; Jun-Ho Lee, PhD;
Sung Kim, PhD; Hong Man Yoon, MD; Bang Wool Eom, PhD; Min-Gew Choi, PhD; Beom Su Kim, PhD; Oh Jeong, PhD; Yun-Suhk Suh, PhD;
Moon-Won Yoo, PhD; In Seob Lee, PhD; Mi Ran Jung, PhD; Ji Yeong An, PhD; Hyoung-Il Kim, PhD; Youngsook Kim, BS; Hannah Yang, BS;
Byung-Ho Nam, PhD; for the FAIRY Study Group

Supplemental content
IMPORTANCE Acute isovolemic anemia occurs when blood loss is replaced with fluid. It is CME Quiz at
often observed after surgery and negatively influences short-term and long-term outcomes. jamanetwork.com/learning

OBJECTIVE To evaluate the efficacy and safety of ferric carboxymaltose to treat acute
isovolemic anemia following gastrectomy.

DESIGN, SETTING, AND PARTICIPANTS The FAIRY trial was a patient-blinded, randomized, phase
3, placebo-controlled, 12-week study conducted between February 4, 2013, and December 15,
2015, in 7 centers across the Republic of Korea. Patients with a serum hemoglobin level of 7 g/dL
to less than 10 g/dL at 5 to 7 days following radical gastrectomy were included.

INTERVENTIONS Patients were randomized to receive a 1-time or 2-time injection of 500 mg

or 1000 mg of ferric carboxymaltose according to body weight (ferric carboxymaltose group,
228 patients) or normal saline (placebo group, 226 patients).

MAIN OUTCOMES AND MEASURES Theprimaryendpointwasthenumberofhemoglobinresponders,

defined as a hemoglobin increase of 2 g/dL or more from baseline, a hemoglobin level of 11 g/dL
or more, or both at week 12. Secondary end points included changes in hemoglobin, ferritin,
and transferrin saturation levels over time, percentage of patients requiring alternative anemia
management (oral iron, transfusion, or both), and quality of life at weeks 3 and 12.

RESULTS Among 454 patients who were randomized (mean age, 61.1 years; women, 54.8%;
mean baseline hemoglobin level, 9.1 g/dL), 96.3% completed the trial. At week 12, the number of
hemoglobin responders was significantly greater for ferric carboxymaltose vs placebo. Compared
with the placebo group, patients in the ferric carboxymaltose group experienced significantly
greater improvements in serum ferritin level and transferrin saturation level; but there were no
significant differences in quality of life. Patients in the ferric carboxymaltose group required less
alternative anemia management than patients in the placebo group. The total rate of adverse
events was higher in the ferric carboxymaltose group than the placebo group, but no severe
adverse events were reported in either group.
Absolute Difference
Outcomes at Week 12 Ferric Carboxymaltose Placebo (95% CI) P Value
Hemoglobin responders, No. (%) 200 (92.2) 115 (54.0) 38.2 (33.6-42.8) .001
Serum ferritin level, ng/mL 233.3 53.4 179.9 (150.2-209.5) .001 Author Affiliations: Author
Transferrin saturation level, % 35.0 19.3 15.7 (13.1-18.3) .001 affiliations are listed at the end of this
article.
Alternative anemia management, % 1.4 6.9 5.5 (3.3-7.6) .006
Group Information: The FAIRY Study
Adverse event rate, No. (%) 15 (6.8) 1 (0.4)
Group members are listed at the end
of this article.
CONCLUSION AND RELEVANCE Among adults with isovolemic anemia following radical Corresponding Author: Young-Woo
gastrectomy, the use of ferric carboxymaltose compared with placebo was more likely to Kim, MD, PhD, FRCS, Department of
Cancer Control and Population
result in improved hemoglobin response at 12 weeks. Health, Graduate School of Cancer
Science and Policy, 323 Ilsan-ro,
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01725789 Ilsandonggu, Goyang 10408,
JAMA. 2017;317(20):2097-2104. doi:10.1001/jama.2017.5703 Republic of Korea (gskim@ncc.re.kr).

(Reprinted) 2097
© 2017 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/936247/ by a University of California - San Diego User on 05/23/2017

 Research Original Investigation
P
erioperative anemia occurs in 25% to 75% of patients
with cancer, and the prevalence of anemia in the im-
mediate postoperative period after major surgery is as
high as 90%.1,2 Postoperative acute isovolemic anemia, which
results from operation-related or trauma-related blood loss,
can adversely affect recovery and quality of life (QOL) by sub-
tly slowing reaction time, deteriorating memory, and decreas-
ing energy levels.3,4 Patients with gastric cancer who un-
dergo gastrectomy are particularly affected by acute isovolemic
anemia because of their decreased ability to absorb iron.5 Some
patients are unable to recover depleted iron stores and de-
velop chronic anemia as a sequel to acute isovolemic anemia.6
Moreover, a study found that anemia was the strongest prog-
nostic factor for lower survival rates compared with those of
patients with regular hemoglobin levels.7
Despite the high prevalence and poor outcome of ane-
mia, blood management has been overlooked due to 2 main
reasons. First, oral iron supplementation immediately after gas-
trectomy can aggravate gastrointestinal dysfunction, leading
to the decision to wait for spontaneous recovery. Second, the
controversial practice of blood transfusion is widespread and
frequently part of the standard of care for patients with
anemia,3,8 despite its demonstrated inability to replenish iron
stores9 and emerging status as an independent risk factor for
complications and poor survival outcomes.10,11
A previous retrospective study suggested that a greater pro-
portion of patients treated with ferric carboxymaltose, a dextran-
free intravenous iron complex, experienced an effective rever-
sal of acute isovolemic anemia compared with no treatment.6
Compared with oral iron, a high-dose infusion of iron is also as-
sociated with faster and higher replenishment of depleted he-
moglobin and iron levels and is not associated with serious gas-
trointestinal adverse events.12 To our knowledge, however, no
randomized trials have confirmed this observation.
The Ferric Carboxymaltose for Acute Isovolemic Anemia
Following Gastrectomy (FAIRY) randomized clinical trial was
therefore designed to evaluate the efficacy of intravenous fer-
ric carboxymaltose for the treatment of acute isovolemic ane-
mia following gastrectomy for gastric cancer.
Methods
Study Design
This was a multicenter, randomized, patient-blinded, placebo-
controlled, phase 3 study conducted at 7 major institutions in
the Republic of Korea. The study design has been published
previously,13 and the protocol was approved by the institu-
tional review board of the National Cancer Center, Korea, on
November 7, 2012 (NCCCTS-12-644) (Supplement 1). The sta-
tistical analysis plan is available in Supplement 2. Each par-
ticipating center obtained committee approval. The National
Cancer Center was responsible for on-site monitoring of the
study locations to verify the accuracy of the acquired data and
examine whether the study protocol followed regulations.
Signed consent forms were obtained from all participants.
The study was conducted in accordance with the prin-
ciples of the Declaration of Helsinki, the International Confer-
2098 JAMA May 23/30, 2017 Volume 317, Number 20 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/936247/ by a University of California - San Diego User on 05/23/2017
Effects of Ferric Carboxymaltose On Postgastrectomy Anemia
Key Points
Question Does administration of ferric carboxymaltose
effectively improve hemoglobin response in patients presenting
with acute isovolemic anemia following gastrectomy?
Findings In this randomized clinical trial of 454 adults, the use of
ferric carboxymaltose compared with placebo was significantly
more likely to result in an effective hemoglobin response (92.2%
vs 54.0%).
Meaning In patients presenting with acute isovolemic anemia
after gastrectomy, administration of ferric carboxymaltose may
improve hemoglobin response.
ence on Harmonisation of Technical Requirements for Regis-
tration of Pharmaceuticals for Human Use Good Clinical Practice
guidelines, and local and national regulations. An indepen-
dent data and safety monitoring board reviewed the safety data.
Patients
Patients 20 years or older with acute isovolemic anemia (he-
moglobin level, ≥7-<10 g/dL) at 5 to 7 days after gastrectomy for
gastric cancer were eligible for this study. The indicated hemo-
globin range was used to assess for moderate anemia.14 Guide-
lines indicate a need for transfusion if hemoglobin levels fall
below 7 g/dL.15 Levels more than 10 g/dL to 12 g/dL or 13 g/dL
indicate mild anemia, which does not justify the use of intra-
venous iron. Patients were excluded from the study if they
had the following: concurrent medical condition(s) that would
prevent adherence or jeopardize their health; hypersensitivity
to any component of the formulation; active severe infection
or inflammation; receipt of transfusion, erythropoietin-
stimulating agent, or more than 500 mg of intravenous iron
within 4 weeks prior to screening; history of acquired iron over-
load, pregnancy or lactation, decreased renal function (de-
fined as creatinine clearance of <50 mL/min calculated accord-
ing to Cockcroft–Gault [to convert creatinine to μmol/L, multiply
by 88.4]); chronic liver disease or increase in liver enzymes (ala-
nine and aspartate aminotransferase) more than 3 times the up-
per limit of the normal range; American Society of Anesthesi-
ology score of more than 3, Eastern Cooperative Oncology Group
performance status score of more than 1; or participation in any
other interventional study within 1 month prior to screening.
Randomization and Masking
Patients were stratified at each study site during randomiza-
tion based on their clinical stage of gastric cancer (according to
the American Joint Commission on Cancer tumor-node-
metastasis [TNM] system): stage I (does not require adjuvant
chemotherapy after gastrectomy) and stages II through IV
(requires adjuvant or palliative chemotherapy after gastrec-
tomy). Group allocation was randomly assigned (1:1) by a data
management system (Velos eResearch, Velos). A random per-
mutation method with block sizes 2, 4, and 6 were used. The
randomized patients were blinded to their group allocation to
minimize reporting bias for the QOL assessments. The intrave-
nous line was covered with black vinyl to ensure patient blind-
ing, and the placebo was administered over the equivalent
jama.com
 Effects of Ferric Carboxymaltose On Postgastrectomy Anemia
period. The care of patients was standardized between the 2
groups, apart from the delivered treatment. All patients were
informed about the trial by the study investigator or an autho-
rized associate.
Procedures
The experimental group received ferric carboxymaltose
(1000 mg for a body weight of ≥50 kg or 500 mg for a body
weight of <50 kg), and the placebo group received normal sa-
line (0.9% sodium chloride solution; 200 mL for a body weight
of ≥50 kg or 100 mL for a body weight of <50 kg). The 2 cat-
egorized dosages were based on manufacturer’s instructions
and a previous trial indicating its support of fixed, weight-
based dosing compared with the Ganzoni-calculated regimen.16
Patients with a serum ferritin level of less than 15 ng/mL (to
convert ferritin to pmol/Lng/mL, multiply by 2.247) and a he-
moglobin level less than 10 g/dL received an additional dose
of 500 mg of ferric carboxymaltose or 100 mL of normal sa-
line (placebo) at week 3. Ferric carboxymaltose was adminis-
tered as a single intravenous drip infusion mixed with 100 mL
or 200 mL of normal saline or an undiluted bolus injection with
an administration time of 15 minutes for 1000 mg or 6 min-
utes for 500 mg.
Outcomes
The primary efficacy end point was the number of hemoglo-
bin responders by week 12. Hemoglobin responders were de-
fined as patients who achieved an increase in hemoglobin lev-
els of 2 g/dL or more14 from baseline to week 12, hemoglobin
levels of 11 g/dL or more at week 12, or both.16 Secondary ef-
ficacy end points were the percentage of patients with hemo-
globin levels of 10 g/dL or more, 11 g/dL, and 12 g/dL by weeks
3 and 12, the percentage of patients requiring alternative ane-
mia management therapy, self-reported QOL assessments at
weeks 3 and 12, and changes in hemoglobin, ferritin, and trans-
ferrin saturation (TSAT) levels over the study duration.
QOL was assessed using the European Organization for
Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire-Core 30 (QLQ-C30), version 3.0, and the gas-
tric cancer–specific module QLQ-STO2217 at baseline and weeks
3 and 12. The EORTC QLQ-C30 is a brief, validated, self-
reporting, cancer-specific measure of QOL comprised of the
following: multiple scales that evaluate physical, role, emo-
tional, cognitive, and social functioning; 1 global health status/
QOL scale; 3 symptom scales measuring fatigue, pain, and nau-
sea or vomiting; 6 single units assessing other symptoms
(dyspnea, insomnia, appetite loss, constipation, and diar-
rhea); and financial difficulties. The EORTC QLQ-STO22 is a
22-item questionnaire that incorporates 5 multi-item scales
(dysphagia, pain, reflux, eating, and anxiety) and 4 questions
covering disease, treatment-related symptoms, and specific
emotional consequences of gastric cancer. The QLQ-C30 and
QLQ-STO22 questionnaires were scored according to the
EORTC scoring manual and converted to a scale of 0 to 100;
higher scores indicated healthier functioning for functional
scales or worsening symptomatology for symptom scales. A
10-point difference in the mean score was accepted as a mini-
mal clinically important difference in health-related QOL.
jama.com
© 2017 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/936247/ by a University of California - San Diego User on 05/23/2017
Original Investigation Research
Safety and tolerability were monitored throughout the
study. Stopping rules of the study medication did not apply ow-
ing to the single administration of ferric carboxymaltose. In the
potential case of hypersensitivity or anaphylactic reactions, im-
mediate interruption of infusion was mandatory. Further man-
agement was left to the discretion of the physician on duty.
Post hoc, exploratory subgroup analyses of hemoglobin re-
sponders were performed according to various clinicopatho-
logical factors relevant to changes in hemoglobin: chemo-
therapy required or not required, type of operation, serum
ferritin level less than 30 ng/mL or 30 ng/mL or more, and TSAT
less than 20% or 20% or more at week 12.
Statistical Analysis
The sample size was calculated based on a superiority design
assuming ferric carboxymaltose response (according to pri-
mary end point definition) of 75% by week 12 and a response
of 60% in the placebo group by week 12. The expected rate of
improvement for patients in the ferric carboxymaltose group
is at least 15% higher (ie, 75% hemoglobin responders) com-
pared with the placebo group. We used 15% as a minimal clini-
cally important difference due to a published document sub-
mitted for approval of ferric carboxymaltose by the US Food
and Drug Administration (FDA).18 Using these estimates, 400
patients were required to detect a significant difference at the
5% level with 90% power:
n = f(α, β) × [p1 × (100 − p1) + p2 × (100 − p2)]/(p2 − p1)2
where p1 and p2 are the percentage “success” in the pla-
cebo group (p1) and ferric carboxymaltose group (p2)
and f(α, β) = [Φ–1(α/2) + Φ–1(β)].2
To account for potential patient dropouts, the sample size
was estimated at 450 patients (225 per group). The number of
missing data was small (0.7% at week 3 and 1.8% at week 12)
and therefore excluded from analysis.19 Modified intention-
to-treat analysis, which excluded missing cases, was per-
formed with the full analysis set, which involved patients who
had results of at least 1 postbaseline hemoglobin measure-
ment among the safety set.
Baseline characteristics and iron parameters were ana-
lyzed using the Pearson χ2 test or 2-tailed Fisher exact test (pa-
tients’ age and sex, clinicopathological data, and morbidity)
and a t test (hemoglobin level before treatment and hospital
days after treatment). The z score test was used to determine
whether a significant difference existed between the 2 groups
with respect to the changes in hemoglobin level during follow-
up. Odds ratios (ORs) were derived from univariable analysis
because baseline variables were well matched, with the ex-
ception of hemoglobin. Post hoc multivariable Cox propor-
tional hazard was implemented to adjust for difference in base-
line hemoglobin values.
The linear mixed model was used to calculate the QOL dif-
ferences between the groups over time.18 Baseline scores and
the interaction between time and group were also included in
the linear mixed model. Covariables such as sex and age of pa-
tients were not included in the model as there were no differ-
ences between the 2 groups.
A post hoc t test was performed to compare effects of fer-
ric carboxymaltose vs placebo on hospital length of stay, and
(Reprinted) JAMA May 23/30, 2017 Volume 317, Number 20 2099
 Research Original Investigation Effects of Ferric Carboxymaltose On Postgastrectomy Anemia

linear mixed-effects modeling was performed with site and

Figure 1. Flow of Patients Through the Study of Ferric Carboxymaltose
stage as the random factors. χ2 and Fisher exact tests were per- for Postgastrectomy Anemia
formed for subgroup analyses. Post hoc χ2 test was used to com-
pare differences in patients who received preoperative oral iron 458 Patients with acute isovolemic anemia
with 4 weeks of surgery and those who did not. Rank sum tests at 5 to 7 days after gastrectomy for
gastric cancer assessed for eligibility
were conducted to evaluate variable distribution due to skew-
ing of data. All tests were 2-sided with a P value of less than
4 Excluded
.05 for significance (MIXED procedure of the SAS program [SAS 1 System error a
Institute], version 14). 3 Did not meet eligibility
criteria

454 Randomized
Results
Patient Disposition 228 Randomized to receive ferric 226 Randomized to receive placebo
Recruitment began on February 4, 2013, and continued through carboxymaltose 112 Had TNM stage I gastric
110 Had TNM stage I gastric cancer
September 21, 2015. A total of 454 patients were enrolled and cancer 114 Had TNM stage II, III, or IV
randomized to receive ferric carboxymaltose (228 patients) or 118 Had TNM stage II, III, or IV gastric cancer
gastric cancer
placebo (226 patients). Only 445 patients (ferric carboxymalt-
ose, 222; placebo, 223) were included in the safety analysis set 222 Received ferric carboxymaltose 223 Received placebo
and 437 in the full analysis set (ferric carboxymaltose, 218 pa- 6 Did not receive ferric 3 Did not receive placebo
carboxymaltose (withdrew 2 Withdrew consent before
tients; placebo, 219 patients) (Figure 1). At baseline, the mean consent before treatment) treatment
age of all patients was 61.1 years, and the mean serum hemo- 1 Not eligible for study
participation (received blood
globin level was 9 g/dL for the ferric carboxymaltose group and transfusion before admission)
9.2 g/dL for the placebo group (P = .01). The mean estimated
blood loss was 187 mL (SD, 175) in the ferric carboxymaltose 5 Did not complete study 10 Did not complete study
group and 192 mL (SD, 167) in the placebo group (P = .72) 1 Withdrew consent after 6 Withdrew consent after
treatment treatment
(Table 1). 3 Lost to follow-up 2 Lost to follow-up
1 Physician withdrew treatment 2 Violation of eligibility criteria
due to surgical complication recognized after treatmen
Primary End Point (received blood transfusion
before treatment)
Among 437 patients of the full analysis set population, the pri-
mary end point was ascertained for 430 patients with a hemo-
222 Included in safety analysis set b 223 Included in safety analysis set b
globin measurement at week 12 (ferric carboxymaltose group,
217 Included in primary end point 213 Included in primary end point
217 patients; placebo group, 213 patients; Figure 1). The num- analysis c analysis c
ber of hemoglobin responders at week 12 was significantly
greater in the ferric carboxymaltose group compared with the TNM indicates tumor-node-metastasis.
placebo group (92.2% [200 patients] in the ferric carboxymalt- a
One systemwide test run conducted prior to randomization of first patient to
ose group vs 54.0% [115 patients] in the placebo group; abso- ensure functional capacity of the eVelos system.
lute difference, 38.2% [95% CI, 33.6% to 42.8%]; P = .001) b
Safety analysis set included patients who received ferric carboxymaltose or
(Table 2). placebo after randomization.
c
At week 12, five patients in the ferric carboxymaltose group lacked a
postbaseline hemoglobin measurement; 10 patients in the placebo group
Secondary Efficacy End Points lacked a postbaseline hemoglobin measurement.
For the secondary analyses, including the QOL measures, there
was no adjustment for multiple comparisons; accordingly,
these findings should be considered exploratory. The propor- maltose group vs 72.3% in the placebo group; absolute differ-
tion of patients who achieved anemia correction and im- ence, 24.9% [95% CI, 20.8%-29.0%], P = .001; 11 g/dL: 88.0%
proved iron parameters all significantly favored ferric carboxy- in the ferric carboxymaltose group vs 46.9% in the placebo
maltose at all time points (eTable 1 in Supplement 3). Compared group; absolute difference, 41.1% [95% CI, 36.4%-45.7%],
with the placebo group, a significantly greater proportion of P = .001; 12 g/dL: 63.6% in the ferric carboxymaltose group vs
patients in the ferric carboxymaltose group obtained hemo- 23.0% in the placebo group; absolute difference, 40.6% [95%
globin levels of 10 g/dL or more, 11 g/dL, and 12 g/dL at week 3 CI, 35.9%-45.2%], P = .001). The difference was more than 20%
(≥10 g/dL: 96.8% in the ferric carboxymaltose group vs 71.1% at all time points, and a nearly 3-fold increase—the greatest dif-
in the placebo group; absolute difference, 25.7% [95% CI, ference achieved—was recorded at week 12 for hemoglobin level
21.6%-29.8%], P = .001; 11 g/dL: 76.0% in the ferric carboxy- of 12 g/dL or more (eTable 1 in Supplement 3).
maltose group vs 41.3% in the placebo group; absolute differ- Significantly more patients in the placebo group required
ence, 34.7% [95% CI, 30.3%-39.2%], P = .001; 12 g/dL: 35.5% alternative anemia management therapy compared with pa-
in the ferric carboxymaltose group vs 12.4% in the placebo tients treated with ferric carboxymaltose (1.4% in the ferric car-
group; absolute difference, 23.1% [95% CI, 19.1%-27.1%], boxymaltose group vs 6.8% in the placebo group; absolute dif-
P = .001) and week 12 (≥10 g/dL: 97.2% in the ferric carboxy- ference, 5.5%, [95% CI, 3.3%-7.6%], P = .006). eTable 2 in

2100 JAMA May 23/30, 2017 Volume 317, Number 20 (Reprinted) jama.com

© 2017 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/936247/ by a University of California - San Diego User on 05/23/2017

 Effects of Ferric Carboxymaltose On Postgastrectomy Anemia Original Investigation Research

Table 1. Baseline Characteristics for Patients With Acute Isovolemic Anemia Following Gastrectomy Receiving
Ferric Carboxymaltose vs Placebo

No. (%)
Total Ferric Carboxymaltose Placebo,
Characteristics (N = 454) (n = 228) (n = 226)
Age, mean (SD), y 61.1 (13.1) 60.9 (13.7) 61.2 (12.6)
Sex
Male 205 (45.2) 103 (45.2) 102 (45.1)
Female 249 (54.8) 125 (54.8) 124 (54.9)
Body weight, mean (SD), kg 57.8 (9.8) 57.6 (9.7) 58.1 (9.9)
Comorbidities
Diabetes 83 (29.7) 39 (29.5) 44 (29.9)
Hypertension 164 (58.8) 74 (56.1) 90 (61.2)
Tuberculosis 31 (11.1) 19 (14.4) 12 (8.2)
Chronic liver disease 1 (0.4) 0 1 (0.7)
Hematologic Values, Mean (SD)a
Preoperative hemoglobin, g/dL 11.7 (1.6) 11.6 (1.6) 11.8 (1.6)
Hemoglobin at enrollment, g/dL 9.1 (0.7) 9.0 (0.7) 9.2 (0.7)
Serum ferritin, ng/mL 126.5 (115.1) 115.9 (104.8) 137.1 (123.9)
Iron, μg/dL 24.3 (13.3) 24.6 (15.2) 24.0 (11.1)
Total iron-binding capacity, μg/dL 242.1 (57.2) 243.6 (56.2) 240.6 (58.2)
Transferrin saturation, % 10.7 (6.4) 10.8 (7.2) 10.5 (5.4)
Creatinine clearance rate, mg/dL 91.3 (33.6) 91.2 (33.4) 91.4 (33.8)
C-reactive protein, median (Q1-Q3), mg/dL 4.7 (2.6-7.8) 4.3 (2.5-7.1) 5.4 (2.8-8.2)
Surgical Operation Characteristics
Gastrectomy
Total 167 (36.8) 87 (38.2) 80 (35.4)
Partial 287 (63.2) 141 (61.8) 146 (64.6)
Surgical approach
Open gastrectomy 336 (74.0) 171 (75.0) 165 (73.0)
Laparoscopy or robot-assisted gastrectomy 118 (26.0) 57 (25.0) 61 (27.0) Abbreviation: TNM,
Estimated blood loss, mean (SD), mL 188.1 (171.4) 186.5 (175.5) 191.5 (167.2) tumor-node-metastasis.

Intraoperative complications SI conversion factors: To convert

C-reactive protein to nmol/L, multiply
Bleeding 15 (75.0) 9 (75.0) 6 (75.0) by 9.524; creatinine to μmol/L,
Other organ injury 4 (20.0) 2 (16.7) 2 (25.0) multiply by 88.4; ferritin to
Open conversion from laparoscopic surgery 1 (5.0) 1 (8.3) 0 pmol/Lng/mL, multiply by 2.247; iron
and iron-binding capacity to μmol/L,
Gastric Cancer Characteristics multiply by 0.179.
TNM stage a
Baseline hematologic values were
b measured in all randomized patients
I 222 (48.9) 110 (48.3) 112 (49.6)
between 5 to 7 days following
II, III, or IV 232 (51.1) 118 (51.7) 114 (50.4)
gastrectomy (mean [SD]), except
Chemotherapy preoperative hemoglobin.
None 273 (60.1) 136 (59.6) 137 (60.6) b
Clinical gastric tumor staging
Adjuvant 174 (38.3) 86 (37.7) 88 (38.9) according to the American Joint
Commission on Cancer TNM
Palliative 7 (1.6) 6 (2.6) 1 (0.5)
system.

Supplement 3 describes the use of alternative anemia man-
agement therapy (oral iron, transfusion, or both) in the pri-
mary analysis population. No patients received erythropoiesis-
stimulating agents.
At week 3, the increase in hemoglobin levels was signifi-
cantly greater in the ferric carboxymaltose group (2.6 g/dL) than
the placebo group (1.4 g/dL; P < .001); and by week 12, the in-
crease in hemoglobin levels was faster in patients treated with
ferric carboxymaltose (3.3 g/dL) than patients treated with pla-
cebo (1.6 g/dL; P < .001) (Figure 2).
At weeks 3 and 12, significant changes in serum ferritin
levels were observed between the ferric carboxymaltose and
placebo groups. Compared with baseline, mean serum ferri-
tin levels increased in the ferric carboxymaltose group, but
decreased in the placebo group (week 3: 508.8 ng/mL in the
ferric carboxymaltose group vs 75.6 ng/mL in the placebo
group; absolute difference, 433.2 ng/mL [95% CI, 381.18-
485.25], P = .001; week 12: 233.3 ng/mL in the ferric carboxy-
maltose group vs 53.4 ng/mL in the placebo group; absolute
difference, 179.9 ng/mL [95% CI, 150.2-209.5], P = .001).

jama.com (Reprinted) JAMA May 23/30, 2017 Volume 317, Number 20 2101

© 2017 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/936247/ by a University of California - San Diego User on 05/23/2017

 Research Original Investigation Effects of Ferric Carboxymaltose On Postgastrectomy Anemia

Table 2. Primary Analysis of Patients With Acute Isovolemic Anemia Following Gastrectomy Receiving Ferric
Carboxymaltose vs Placebo By Week 12

Total Patients in Primary Hb Responders, No. (%)b Absolute

Analysis, No. (%) Ferric Carboxymaltose Placebo Difference, %
(N = 430)a (n = 217) (n = 213) (95% CI)
Abbreviation: Hb, hemoglobin.
Hb increase of ≥2 g/dL 315 (73.3) 200 (92.2) 115 (54.0) 38.20 a
from baseline, Hb level (33.6-42.8) No. of patients with an Hb
of ≥11 g/dL, or both measurement at 12 weeks.
(primary outcome) b
Hb responder was defined as a
Hb increase of ≥2 g/dL from 277 (64.4) 191 (88.0) 86 (40.4) 47.60 hemoglobin increase of 2 g/dL or
baseline (42.9-52.4)
more from baseline, a hemoglobin
Hb level of ≥11 g/dL 291 (67.7) 191 (88.0) 100 (46.0) 41.10 level of 11 g/dL or more, or both at
(36.4-45.7) week 12.

and urticaria in 5 patients (2.3%); all other adverse events

Figure 2. Hemoglobin Levels Among Patients Receiving Ferric
Carboxymaltose vs Placebo Over Time were reported in 1 patient in each group (0.5%) (eTable 3 in
Supplement 3). All adverse events were reported as a grade 1
16 severity except injection site reactions and urticaria, which
Ferric carboxymaltose were reported as grades 1 and 2. Other reported study drug–
14 Placebo related adverse events included constipation, fever, head-
Hemoglobin Level, g/dL

ache, insomnia, and phlebitis. Otherwise, ferric carboxymalt-

12 ose was well tolerated with no serious adverse events, such
as hypersensitivity or anaphylactic reactions (eTable 4 in
10 Supplement 3). No patients received an undiluted bolus
injection, and 1 patient received an additional dose of ferric
8
carboxymaltose at week 3.

Post Hoc Analysis

6
Screening and 3 wk
Baseline
No. of participants
Ferric carboxymaltose 228 217
Placebo 226 218
The solid line in each box indicates the median. The top line of the box indicates
the 75th percentile, and the bottom line of the box indicates the 25th
percentile. The top and bottom whiskers indicate the upper and lower adjacent
values, respectively. The circles represent the outlier values.
Significant changes were also observed in transferrin
saturation levels (week 3: 29.8% in the ferric carboxymalt-
ose group vs 13.9% in the placebo group; absolute differ-
ence, 15.9% [95% CI, 14.1%-17.7%], P = .001; week 12: 35.0%
in the ferric carboxymaltose group vs 19.3% in the placebo
group; absolute difference, 15.7% [95% CI, 13.1%-18.3%],
P = .001).
QOL Assessments With EORTC QLQ-C30 and QLQ-STO22
The overall proportion of completed QOL assessments was
greater than 95% at all time points (96.9% at week 3; 95.4%
at week 12). No significant difference was observed in the
global health status/QOL scale at weeks 3 and 12. The pre-
defined 10-point minimal clinical difference was not met,
and therefore no clinical significance was observed (eTable 3
in Supplement 3).
12 wk Hemoglobin response was significantly greater in the ferric
carboxymaltose group compared with the placebo group in
217 all exploratory subgroups (eFigure 2 in the Supplement).
213 Analysis comparing the effects of ferric carboxymaltose vs
placebo on mean hospital length of stay was not statistically
significant (ferric carboxymaltose group, 10.7 days [SD, 7.9];
placebo group, 10.9 days [SD, 13.8]; difference, 0.2 days
[95% CI, −2.341 to 1.789], P = .79). Analysis of hemoglobin
response in patients who received preoperative oral iron
within 4 weeks before enrollment compared with those who
did not was not statistically significant (2.4% of randomized
patients; 4 of 4 patients in the ferric carboxymaltose group
and 3 of 7 patients in the placebo group; P = .47); therefore,
preoperative oral iron was not associated with measured
end points as a confounder. After adjusting for potentially
significant baseline differences, multivariable analysis
showed that the ferric carboxymaltose group experienced a
significantly greater proportion of hemoglobin responders
compared with the placebo group (OR, 12.08 [95% CI, 6.70
to 21.78]; P < .001) (eTable 5 in Supplement 3). Results of the
linear mixed model were similar to results from analysis of
the primary end point (OR, 10.10 [95% CI 5.73 to 17.81];
P < .001).

Safety and Tolerability of Ferric Carboxymaltose

The total rate of adverse events was higher in the ferric
carboxymaltose group than the placebo group (ferric car-
boxymaltose group, 15 patients [6.8%]; placebo group, 1
patient [0.4%]). Ferric carboxymaltose–related adverse
events included injection site reactions in 5 patients (2.3%)
Discussion
In this randomized clinical trial of patients with isovolemic
anemia following gastrectomy, a 1-time or 2-time infusion of
either 500 mg or 1000 mg of ferric carboxymaltose com-
pared with placebo significantly increased serum hemoglo-
bin levels in 92.2% patients in the ferric carboxymaltose

2102 JAMA May 23/30, 2017 Volume 317, Number 20 (Reprinted) jama.com

© 2017 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/936247/ by a University of California - San Diego User on 05/23/2017

 Effects of Ferric Carboxymaltose On Postgastrectomy Anemia Original Investigation Research

group vs 54.0% of patients in the placebo group (P = .001).
The results of the secondary end points were consistent with
the primary end point and demonstrated increased hemoglo-
bin and iron levels over time, decreased need for alternative
treatments for anemia. The benefits of this short and easily ad-
ministered therapy were immediate and sustained as mea-
sured through increased hemoglobin and iron levels over
time and a decreased need for alternative treatments for ane-
mia. Overall, there was no clinically significant difference in
QOL at weeks 3 and 12. Post hoc analysis showed improved he-
moglobin response to ferric carboxymaltose in all explor-
atory subgroups.
Treatment with ferric carboxymaltose was also associ-
ated with minimal toxicity and was well tolerated. To date,
more than 3600 patients have been treated with ferric car-
boxymaltose in various clinical trials, and the replenishment
of iron stores with minimal adverse effects has been consis-
tently reported.12,20 In a previous study that evaluated the
safety profile of a pooled database of 5799 patients exposed
to 750 mg of ferric carboxymaltose, only low-grade and tran-
sient adverse events were reported in at least 1% of patients
who were treated.18 Commonly reported adverse events in-
cluded injection-site reactions, nausea, constipation, head-
ache, and diarrhea. Similar to this study, all adverse events
were mild to moderate in severity (grade 1 or 2) with no grade
3 or 4 reactions.
QOL measurements over time showed ferric carboxy-
maltose–related improvements in fatigue and dyspnea but did
not meet the predefined clinically relevant QOL improve-
ment criterion. This may be because the patients were en-
rolled into this study immediately after receiving a major sur-
gery, and there may be confounding factors influencing QOL
that could not be distinguished by the questionnaires.
Limitations
This study has several limitations. First, the results of the sec-
ondary analyses and post hoc subgroup analysis were explor-
atory in nature and should be viewed as hypotheses. Further
studies are needed to confirm these findings. Second, the ef-
fect of ferric carboxymaltose on long-term survival is consid-
ered hypothesis-generating, and there may be hidden com-
plications that have not yet been determined.21 Future studies
should be directed toward analyzing the long-term effects of
ferric carboxymaltose.
Conclusion
Among adults with isovolemic anemia following radical
gastrectomy, the use of ferric carboxymaltose compared with
placebo was more likely to result in improved hemoglobin re-
sponse at 12 weeks.

ARTICLE INFORMATION
Accepted for Publication: April 24, 2017.
Author Affiliations: Department of Cancer Control
and Population Health, Graduate School of Cancer
Science and Policy, National Cancer Center, Goyang,
Republic of Korea (Y.-W. Kim); Center for Gastric
Cancer, Research Institute and Hospital, National
Cancer Center, Goyang, Republic of Korea
(Y.-W. Kim, K. W. Ryu, Yoon, Eom, Y. Kim, H. Yang);
Center for Gastric Cancer, Samsung Medical Center,
Sungkyunkwan University School of Medicine,
Seoul, Republic of Korea (Bae, Sohn, J.-H. Lee,
S. Kim, Choi, An); Department of Gastroenterologic
Surgery, Chonnam National University Hwasun
Hospital, Hwasun County, Republic of Korea (Park,
S. Y. Ryu, Jeong, Jung); Department of Surgery,
Seoul National University College of Medicine,
Seoul, Republic of Korea (H.-K. Yang, H.-J. Lee,
Suh); Center for Gastric Cancer, Gastric Cancer
Center, Kyungpook National University Medical
Center, Daegu, Republic of Korea (Yu, Kwon);
Center for Gastric Cancer, Asan Medical Center,
University of Ulsan College of Medicine, Seoul,
Republic of Korea (Yook, B. S. Kim, Yoo, I. S. Lee);
Department of Gastrointestinal Surgery, Yonsei
University Health System, Seoul, Republic of Korea
(Noh, H.-I. Kim); Cancer Registration and
Biostatistics Branch, Center for Clinical Trials,
National Cancer Center, Goyang, Republic of Korea
(Han, Nam).
Author Contributions: Dr Y.-W. Kim had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis. Drs Y-W Kim and Bae
contributed equally as primary authors.
Concept and design: Y.-W. Kim, Bae, Park, H.-K.
Yang, Yu, Yook, Noh, Y. Kim, Nam.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: Y.-W. Kim, Bae, Yu, Han, H.
Yang, Y. Kim, Nam.
Statistical analysis: Y.-W. Kim, Han, Y. Kim, Nam.
Obtained funding: Y.-W. Kim.
Administrative, technical, or material support: Y.-W.
Kim, Bae, Park, H.-K. Yang, Yu, Yook, Noh, Y. Kim,
Nam.
Supervision: Y.-W. Kim, Bae, Park, H.-K. Yang, Yu,
Yook, Noh, Y. Kim, Nam.
Manuscript revisions: Y.-W. Kim, Y. Kim, H. Yang.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Funding/Support: This investigator-initiated trial
was funded by JW Pharmaceutical and Vifor
Pharma. Employees of the National Cancer Center,
Korea, collected, managed, and analyzed data with
partial support from grants NCC-1410130 and
NCC-1710120 from the National Cancer Center,
which are internal sources of funding dispensed to
employees regardless of research type.
Role of the Funder/Sponsor: Vifor Pharma and JW
Pharmaceutical had no role in the design or conduct
of the study; the collection, management, analysis,
or interpretation of the data; or the preparation,
review, approval, and decision to submit the
manuscript for publication.
Group Information: The FAIRY Study Group
members are Young-Woo Kim (principal
investigator [PI] and secretary general); Wansik Yu,
Sung Hoon Noh, Han-Kwang Yang, Jae-Moon Bae,
Young-Kyu Park, and Jeong Hwan Yook (all site PIs);
Sung Kim, Tae Sung Sohn, Keun Won Ryu, Seung
Yeob Ryu, Jun-Ho Lee, Oh Kyoung Kwon,
Hyuk-Joon Lee, Min-Gew Choi, Oh Jeong, Ji Yeong
An, Hong Man Yoon, Hyoung-Il Kim, Bang Wool
Eom, Moon-Won Yoo, Beom Su Kim, Yun-Suhk Suh,
In Seob Lee, and Mi Ran Jung( all investigators);
and Byung-Ho Nam (principal biostatistician).
Additional Contributions: We thank the following
nurses for their support as research coordinators:
Susie Kim, MS (Center for Gastric Cancer, Research
Institute and Hospital), Sang Ae Park, BS (Samsung
Medical Center); Hui Neong Choi, BS (Seoul
National University Hospital), Boram Park, BS
(Chonnam National University Hwasun Hospital),
Seon-Jung Lee, BS (Kyungpook National University
Medical Center), and Yeon-Joo Kim, BS (Yonsei
University Health System), as well as Choon-Sik
Gong, MS (University of Ulsan College of Medicine).
No individual received direct compensation for
involvement in this study.
REFERENCES
1. Gombotz H, Rehak PH, Shander A, Hofmann A.
Blood use in elective surgery: the Austrian
benchmark study. Transfusion. 2007;47(8):1468-
1480.
2. Shander A, Knight K, Thurer R, Adamson J,
Spence R. Prevalence and outcomes of anemia in
surgery: a systematic review of the literature. Am J
Med. 2004;116(suppl 7A):58S-69S.
3. Weiskopf RB, Kramer JH, Viele M, et al. Acute
severe isovolemic anemia impairs cognitive
function and memory in humans. Anesthesiology.
2000;92(6):1646-1652.
4. Weiskopf RB, Feiner J, Hopf HW, et al. Oxygen
reverses deficits of cognitive function and memory

jama.com (Reprinted) JAMA May 23/30, 2017 Volume 317, Number 20 2103

© 2017 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/936247/ by a University of California - San Diego User on 05/23/2017

 Research Original Investigation
and increased heart rate induced by acute severe
isovolemic anemia. Anesthesiology. 2002;96(4):
871-877.
5. Lim CH, Kim SW, Kim WC, et al. Anemia after
gastrectomy for early gastric cancer: long-term
follow-up observational study. World J Gastroenterol.
2012;18(42):6114-6119.
6. Yoon HM, Kim YW, Nam BH, et al. Intravenous
iron supplementation may be superior to
observation in acute isovolemic anemia after
gastrectomy for cancer. World J Gastroenterol.
2014;20(7):1852-1857.
7. Park SH, Nam E, Bang SM, Cho EK, Shin DB,
Lee JH. A randomized trial of anemia correction
with two different hemoglobin targets in the
first-line chemotherapy of advanced gastric cancer.
Cancer Chemother Pharmacol. 2008;62(1):1-9.
8. Adachi Y, Mimori K, Mori M, Maehara Y,
Sugimachi K. Morbidity after D2 and D3
gastrectomy for node-positive gastric carcinoma.
J Am Coll Surg. 1997;184(3):240-244.
9. Koch CG, Li L, Sessler DI, et al. Duration of
red-cell storage and complications after cardiac
surgery. N Engl J Med. 2008;358(12):1229-1239.
10. Weber RS, Jabbour N, Martin RC II. Anemia and
transfusions in patients undergoing surgery for
cancer. Ann Surg Oncol. 2008;15(1):34-45.
2104 JAMA May 23/30, 2017 Volume 317, Number 20 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/936247/ by a University of California - San Diego User on 05/23/2017
Effects of Ferric Carboxymaltose On Postgastrectomy Anemia
11. Hyung WJ, Noh SH, Shin DW, et al. Adverse
effects of perioperative transfusion on patients
with stage III and IV gastric cancer. Ann Surg Oncol.
2002;9(1):5-12.
12. Keating GM. Ferric carboxymaltose: a review of
its use in iron deficiency. Drugs. 2015;75(1):101-127.
13. Reim D, Kim YW, Nam BH, et al. FAIRY:
a randomized controlled patient-blind phase III
study to compare the efficacy and safety of
intravenous ferric carboxymaltose (Ferinject) to
placebo in patients with acute isovolemic anemia
after gastrectomy—study protocol for a randomized
controlled trial. Trials. 2014;15:111.
14. Rizzo JD, Brouwers M, Hurley P, Seidenfeld J,
Somerfield MR, Temin S. American society of
clinical oncology/American society of hematology
clinical practice guideline update on the use of
epoetin and darbepoetin in adult patients with
cancer. J Oncol Pract. 2010;6(6):317-320.
15. Carson JL, Noveck H, Berlin JA, Gould SA.
Mortality and morbidity in patients with very low
postoperative Hb levels who decline blood
transfusion. Transfusion. 2002;42(7):812-818.
16. Evstatiev R, Marteau P, Iqbal T, et al; FERGI
Study Group. FERGIcor, a randomized controlled
trial on ferric carboxymaltose for iron deficiency
anemia in inflammatory bowel disease.
Gastroenterology. 2011;141(3):846-853.e1, 2.
17. Fayers P, Bottomley A; EORTC Quality of Life
Group; Quality of Life Unit; European Organisation
for Research and Treatment of Cancer. Quality of
life research within the EORTC-the EORTC
QLQ-C30. Eur J Cancer. 2002;38(suppl 4):S125-S133.
18. US Food and Drug Administration. Center
for Drug Evaluation and Research: Application
number 203565Orig1s000: Medical Review(s).
https://www.accessdata.fda.gov/drugsatfda_docs
/nda/2013/203565Orig1s000MedR.pdf. Accessed
April 19, 2017.
19. Schafer JL. Multiple imputation: a primer. Stat
Methods Med Res. 1999;8(1):3-15.
20. Bregman DB, Goodnough LT. Experience with
intravenous ferric carboxymaltose in patients with
iron deficiency anemia. Ther Adv Hematol. 2014;5
(2):48-60.
21. Macdougall IC, Bock AH, Carrera F, et al;
FIND-CKD Study Investigators. FIND-CKD:
a randomized trial of intravenous ferric
carboxymaltose versus oral iron in patients with
chronic kidney disease and iron deficiency anaemia.
Nephrol Dial Transplant. 2014;29(11):2075-2084.
jama.com